Endophthalmitis is one of the most sight-threatening complications of ocular surgery or penetrating injury. Despite aggressive therapeutic and surgical intervention, endophthalmitis frequently results in partial to complete loss of vision, often within a few days of infection. The overarching goal of this research is to develop a scientific basis for management of endophthalmitis, based on the optimized use of antimicrobial and anti-inflammatory agents, toward enhancing the recovery of useful vision. The following specific aims of the proposed 5 year continuation period are designed, based on the results from the previous period of support, to advance this goal: Specific Aim 1: Determine the molecular basis of virulence for the most common etiology of endophthalmitis associated with visual loss. Specific Aim 2: Develop a murine model system that permits complete analysis of host and bacterial factors that contribute to the pathogenesis of endophthalmitis, and determine the basis for 1) differences in pathogenesis of endophthalmitis due to virulent and avirulent organisms, 2) differences in the pathogenesis of endophthalmitis when infection is acquired by anterior and posterior routes, and 3) the contribution of immune privilege to the pathogenesis of endophthalmitis and mechanisms by which this may be undermined by specific pathogens. Specific Aim 3: Resolve the current controversy surrounding the use of anti-inflammatory adjunctive therapies in endophthalmitis management, and test new specifically targeted therapies for their value in mitigating visual loss.